1. Technical Field
The present invention generally relates to improving desired effects of a drug taken by a patient, and minimizing undesired effects of the drug, such as by modulation of drug efficacy, side effect profile and therapeutic index of the drug, and more particularly to methods and apparatus employing vagus nerve stimulation to improve the efficacy, side effect profile, and/or therapeutic index of a drug that is administered to an individual for therapeutic purposes.
2. Description of Related Art
The relative safety of a drug is typically indicated by its “therapeutic index,” which is the ratio of the median lethal dose (LD50) to the median medically effective dose (MED50). The therapeutic index of a given drug is desirably a large number (e.g., 10 or more), indicating that the range of therapeutically recommended dosages is much lower than the potentially lethal dosage range. Drugs identified as having a high risk of being involved in a clinically significant adverse effect frequently have a narrow therapeutic index, a very steep dose-response curve or potent pharmacologic effects. A toxic dose of such drugs may be only slightly above the therapeutic dose, in which case even a slight increase in the dose may produce a large increase in serum drug levels and an adverse clinical effect. Conversely, a slight decrease in the plasma level of drugs with a steep dose-response curve may result in a significant loss of therapeutic effect.
Drug interactions and adverse side effects have an enormous impact on treatment and quality of life. An adverse drug reaction can be defined as an unexpected diminished or enhanced pharmacologic activity or toxicity of a drug when used alone, or any noxious response to a drug that occurs at doses used in humans for prophylaxis, diagnosis, or therapy. One approach to mitigating the drug dose-limiting toxicity problem is to administer the primary drug at a lower than optimum dose, together with administration of a second drug with non-overlapping toxicity. Ways to improve the efficacy and therapeutic index of therapeutically useful drugs are sought.
Primary determinants of drug efficacy and therapeutic index are the pharmacologic properties of the drug and also its pharmacokinetic properties, such as absorption, clearance, plasma binding, solubility and volume of distribution, among others, as well as the time periods in which such properties occur. A marked shift in serum drug levels can significantly alter clinical response. Pharmacokinetic properties influence the disposition of a drug in the body and may also affect the effects of one drug on the absorption, distribution, metabolism and/or excretion of other drugs in a person's body.
It is well established from neuroanatomical studies that the vagus nerve has afferent projections into the hypothalamus, brainstem and limbic areas of the brain, which has been corroborated by numerous functional imaging studies. Those regions regulate homeostatic mechanisms such as salt and water balance, digestion (stomach pH) and excretion. Consequently, the pharmacokinetics (i e., absorption, distribution, localization in tissues, biotransformation, excretion, mode of action (MOA), concentration, effect) of an ingested drug is also affected by vagus nerve activity, including absorption, distribution and elimination of the drug. The vagus nerve also has direct efferent projections on target organs involved in homeostasis. For instance, the knowledge of mechanisms involved in osmotic regulation across the intestinal epithelium has been substantially refined over the past two decades. It is known that extrinsic as well as intrinsic innervation of the gut plays a major role in regulating the intestinal absorption of numerous compounds routinely used for the treatment of common diseases is profoundly limited by their physiochemical characteristics. It has also been shown that vagal afferent pathways are active in the inhibition of gastric emptying induced by acid and different food ingredients.
Therapeutic use of VNS has been described for disorders such as medically refractory seizures, which are seizures that occur despite treatment with therapeutic levels of antiepileptic drugs. VNS has also been approved for treatment of seizures in individuals that cannot be treated with therapeutic levels of antiepileptic drugs due to intolerable adverse side effects of the drugs, and for depression in patients who have failed to achieve significant benefits from drug therapies. VNS has also been described and continues to be investigated for treatment of eating disorders such as bulimia, anorexia and obesity, and for traumatic brain injury including stroke.